RGD Reference Report - The regulation of ribonucleoside diphosphate reductase by the tumor promoter orotic acid in normal rat liver in vivo. - Rat Genome Database

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The regulation of ribonucleoside diphosphate reductase by the tumor promoter orotic acid in normal rat liver in vivo.

Authors: Manjeshwar, S  Rao, PM  Rajalakshmi, S  Sarma, DS 
Citation: Manjeshwar S, etal., Mol Carcinog. 1999 Mar;24(3):188-96.
RGD ID: 5133695
Pubmed: PMID:10204803   (View Abstract at PubMed)

Our earlier studies have shown that in normal hepatocytes, orotic acid (OA) inhibits DNA synthesis induced by several growth factors in vitro and after two-thirds partial hepatectomy (PH) in vivo. As in the normal liver OA induces an imbalance in nucleotide pools (specifically, an increase in uridine nucleotides, including deoxyuridine nucleotides, and a decrease in adenosine nucleotides, including ATP) and creation of this imbalance is crucial for the mitoinhibitory effects of OA, we hypothesized that ribonucleoside diphosphate reductase (RNR), a key enzyme in DNA synthesis that is regulated by nucleotide/deoxynucleotide levels, might be one of the targets for the inhibition of DNA synthesis by OA. To test this hypothesis, we subjected male Fischer 344 rats (130-150 g) to two-thirds PH in the absence or in the presence of OA (a 300-mg tablet of OA methyl ester implanted intraperitoneally at the time of two-thirds PH). The rats were killed at different times later, and their livers were processed for analysis of levels of RNR enzyme activity, protein, and mRNA transcripts. The results obtained indicated that treatment with OA resulted in a near-100% inhibition of RNR induced by two-thirds PH in rat liver, as monitored by enzyme activity and protein level. Furthermore, this inhibition was paralleled by a decrease in the mRNA transcripts for both the M1 and M2 subunits of RNR. Nuclear run-off assays indicated that this decrease in the levels of mRNA transcripts could not be attributed to an effect on transcription. However, administration of OA 20 h after two-thirds PH, when RNR mRNA transcripts were maximally induced, resulted in increased degradation of the RNR M1 and M2 subunits. Taken together, these results indicate that OA treatment decreases RNR levels induced by two-thirds PH, at the levels of enzyme activity, protein, and mRNA transcripts, and the decreased levels of mRNA transcripts appeared to be due to increased degradation of the transcripts.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Rrm1Ratpyrimidine nucleobase metabolic process  IEP orotic acidRGD 
Rrm2Ratpyrimidine nucleobase metabolic process  IEP orotic acidRGD 

Objects Annotated

Genes (Rattus norvegicus)
Rrm1  (ribonucleotide reductase catalytic subunit M1)
Rrm2  (ribonucleotide reductase regulatory subunit M2)


Additional Information